Identification and characterization of putative methylation targets in the MAOA locus using bioinformatic approaches.
Identification and characterization of putative methylation targets in the MAOA locus using bioinformatic approaches.
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DOI：
10.4161/epi.5.4.11719
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发表时间：
2010-05-16
期刊：
影响因子：
3.7
通讯作者：
Fowler JS
中科院分区：
文献类型：
--
作者：
Shumay E;Fowler JS
单胺氧化酶A （MAO A）是一种催化神经递质胺氧化的酶。人类MAOA基因的功能多态性（高MAOA和低MAOA）与不同的行为表型有关。为了直接研究这种多态性影响脑功能的生物学机制，我们最近在健康志愿者中测量了MAO A酶的活性。当发现个体大脑MAOA水平与MAOA基因型之间没有关系时，我们假设存在控制MAOA表达的额外调节机制。鉴于DNA甲基化与基因表达调控有关，我们假设表观遗传机制影响MAOA的表达。我们低估的假设是，个体基因型的差异在MAOA位点的表观遗传潜力中起着关键作用，因此，决定了个体大脑中MAO a活性的水平。作为实验验证假设的第一步，我们进行了全面的生物信息学分析，旨在询问可能调节其表观遗传敏感性的MAOA位点的基因组特征和属性。研究发现：(1)扩展的MAOA调控区包含两个CpG岛（cgi），其中一个与典型MAOA启动子重叠，另一个位于更远的上游；两种cgi都表现出对差异甲基化的敏感性。(2) uVNTR对MAOA转录活性的影响可能具有表观遗传性质：该多态性区域位于MAOA的CGI中，其本身含有CpGs，因此，重复增量的数量有效地改变了MAOA启动子中可甲基化胞嘧啶的数量。一系列的计算机分析（核小体定位、局部DNA的物理性质、转录因子结合位点的聚类）、组蛋白修饰和Pol 2位点的实验数据以及来自RefSeq mRNA文库的数据共同表明，MAOA基因可能有一个替代启动子。基于我们的研究结果，我们提出了一种人类MAOA的调控机制，根据该机制，MAOA在体内的表达是通过由替代启动子（cgi相关）启动的组织特异性转录物的产生来执行的，其中特定启动子的转录激活受到表观遗传控制。
Monoamine oxidase A (MAO A) is an enzyme that catalyzes the oxidation of neurotransmitter amines. A functional polymorphism in the human MAOA gene (high- and low- MAOA) has been associated with distinct behavioral phenotypes. To investigate directly the biological mechanism whereby this polymorphism influences brain function, we recently measured the activity of the MAO A enzyme in healthy volunteers. When found no relationship between the individual's brain MAO A level and the MAOA genotype, we postulated that there are additional regulatory mechanisms that control the MAOA expression. Given that DNA methylation is linked to the regulation of gene expression, we hypothesized that epigenetic mechanisms factor into the MAOA expression. Our underplaying assumption was that the differences in an individual's genotype play a key role in the epigenetic potential of the MAOA locus and, consequently, determine the individual's level of MAO A activity in the brain. As a first step towards experimental validation of the hypothesis, we performed a comprehensive bioinformatic analysis aiming to interrogate genomic features and attributes of the MAOA locus that might modulate its epigenetic sensitivity. Major findings of our analysis are the following: (1) the extended MAOA regulatory region contains two CpG islands (CGIs), one of which overlaps with the canonical MAOA promoter and the other is located further upstream; both CGIs exhibit sensitivity to differential methylation. (2) The uVNTR's effect on the MAOA's transcriptional activity might have epigenetic nature: this polymorphic region resides within the MAOA's CGI and itself contains CpGs, thus, the number of repeating increments effectively changes the number of methylatable cytosines in the MAOA promoter. An array of in silico analyses (the nucleosome positioning, the physical properties of the local DNA, the clustering of transcription-factor binding sites) together with experimental data on histone modifications and Pol 2 sites and data from the RefSeq mRNA library together suggest that the MAOA gene might have an alternative promoter. Based on our findings, we propose a regulatory mechanism for the human MAOA according to which the MAOA expression in vivo is executed by the generation of tissue-specific transcripts initiated from the alternative promoters (both CGI-associated) where transcriptional activation of a particular promoter is under epigenetic control.